Blood–Brain Barrier Dynamics to Maintain Brain Homeostasis

Segarra, Marta; Aburto, María Rodríguez; Acker‐Palmer, Amparo

doi:10.1016/j.tins.2020.12.002

Cited by 177 publications

(120 citation statements)

References 135 publications

(155 reference statements)

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“…In addition, the BBB, which normally separates CNS and peripheral cholesterol, has been shown to lose integrity during aging ( Montagne et al, 2015 ). This might affect brain cholesterol levels especially in the hippocampus where BBB break-down has been reported to occur first ( Montagne et al, 2015 ; Segarra et al, 2021 ). Indeed in mice, BBB breakdown results in entry of peripheral cholesterol into the brain, and reversely BBB breakdown also led to increased release of 24S-OHC from the brain into the circulation ( Saeed et al, 2014 ).…”

Section: Brain Cholesterol Metabolism; Changes From Development To Agingmentioning

confidence: 99%

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Feringa

Kant

2021

Front. Aging Neurosci.

151

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While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer’s disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.

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Section: Brain Cholesterol Metabolism; Changes From Development To Agingmentioning

confidence: 99%

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Feringa

Kant

2021

Front. Aging Neurosci.

151

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“…Different vascular elements become dysfunctional during natural aging and alterations include increased permeability, ECM remodeling, altered BBB transport, endothelial and pericyte degeneration, and astrocyte malfunctioning. Hence, barrier integrity appears compromised in aged individuals, leading to abnormal trespassing of blood-borne proteins and impairment of blood flow regulation (Obermeier et al, 2013;Segarra et al, 2021). The described changes during aging, not only alter signaling interactions between vascular elements and NSCs, but also limit the supply of nutrients and oxygen and expose the niche to pro-aging circulating factors (Figure 3B; Silva-Vargas et al, 2013;Apple and Kokovay, 2017;Smith et al, 2018).…”

Section: The Neurogenic Vascular Microenvironment and Its Transformation Over Timementioning

confidence: 99%

Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

et al. 2021

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The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.

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“…Transportation of substances and biomolecules plays a role in maintaining organ functions, including the brain [ 130 ] and liver [ 131 ]. Selective transportation of these molecules via the apical-basolateral axis of many organs mainly relies on intercellular junctions of epithelial and endothelial cells.…”

Section: Opportunities and Challenges In The Use Of The Liver-on-a-chip In Personalized Medicinementioning

confidence: 99%

Progress and Challenges in the Use of a Liver-on-a-Chip for Hepatotropic Infectious Diseases

Kulkeaw

Pengsart

2021

Micromachines

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The liver is a target organ of life-threatening pathogens and prominently contributes to the variation in drug responses and drug-induced liver injury among patients. Currently available drugs significantly decrease the morbidity and mortality of liver-dwelling pathogens worldwide; however, emerging clinical evidence reveals the importance of host factors in the design of safe and effective therapies for individuals, known as personalized medicine. Given the primary adherence of cells in conventional two-dimensional culture, the use of these one-size-fit-to-all models in preclinical drug development can lead to substantial failures in assessing therapeutic safety and efficacy. Advances in stem cell biology, bioengineering and material sciences allow us to develop a more physiologically relevant model that is capable of recapitulating the human liver. This report reviews the current use of liver-on-a-chip models of hepatotropic infectious diseases in the context of precision medicine including hepatitis virus and malaria parasites, assesses patient-specific responses to antiviral drugs, and designs personalized therapeutic treatments to address the need for a personalized liver-like model. Second, most organs-on-chips lack a monitoring system for cell functions in real time; thus, the review discusses recent advances and challenges in combining liver-on-a-chip technology with biosensors for assessing hepatocyte viability and functions. Prospectively, the biosensor-integrated liver-on-a-chip device would provide novel biological insights that could accelerate the development of novel therapeutic compounds.

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Blood–Brain Barrier Dynamics to Maintain Brain Homeostasis

Cited by 177 publications

References 135 publications

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

Progress and Challenges in the Use of a Liver-on-a-Chip for Hepatotropic Infectious Diseases

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